Nearly all humans have atherosclerotic plaque, but only a subset of us will experience its most perilous effects-a heart attack or stroke. Atherosclerosis accounts for thirty percent of worldwide deaths and brings a financial burden greater than all cancers combined an estimated $300 billion per year in the United States. The key to lessening the burden and limiting the vast number of deaths is to determine which of us are at risk so they can be medically treated to prevent heart attack, stroke, and death. Doctors rely on information gained from imaging studies such as magnetic resonance imaging (MRI) to make treatment decisions aimed at improving patient quality of life and lifespan. With this project, we aim to create a contrast agent for MRI that more effectively detects the most dangerous plaques that cause heart attacks and strokes. The studies proposed here are aimed at filling the void in our clinical ability to assess patient risk for heart attack and stroke by creating a contrast agent capable of functionally determining plaque severity with an 'on-switch' triggered by a critical process in atherosclerosis known as oxidative stress. The contrast agent becomes visible on the MR image at the disease site when superoxides present during oxidative stress disassemble the polymer coating that up until the point had masked the contrast agent. First, we will create and evaluate a nanoparticle comprised of a contrast agent shielded within a polymer coating. The polymer coating makes the contrast agent invisible to MR, as is desired in our design until such time as the agent reaches the disease site. Second, we will evaluate whether the polymer coating disintegrates in the presence of superoxide molecules (similar to those present in atherosclerosis) in a way that allows the contrast agent to become visible to MRI. Third, we will evaluate whether the nanoparticles exhibit the same superoxide-triggered contrast in the presence of superoxides produced by human cells. We will also evaluate the levels of toxicity of the nanoparticle to human cells. With these steps, we expect to move the field towards: more accurate assessment of plaque severity via a functionally-based contrast mechanism, better informed clinical decisions, and ultimately improved patient health.